More than 20% of the glucose used by the body is consumed by the brain, thus, any alteration in the physiological process associated with glucose metabolism and energy regulation can have deleterious effects on brain functioning. Emerging data indicate that acute and chronic exposure to cocaine alters metabolic and bioenergetic pathways in the brain as well as in other organs and affects mitochondria function and ATP production. Cocaine abuse is a significant risk factor for becoming infected with HIV-1 and studies show that in combination, cocaine and HIV-1 lead to significantly greater damage to the CNS. In this context, our recent studies point to the negative impact of HIV-1 infection on glycolytic pathways in macrophages, which is beneficial for viral replication, and the ability of HIV-1 Tat released by the infected macrophages and microglia to disturb the integrity of mitochondrial DNA bioenergetic pathways and mitochondria turnover in neuronal cells. All of these observations along with previous reports on the ability of cocaine and HIV-1 Tat to induce production of mitochondrial reactive oxygen species (ROS) provides a rationale for us to hypothesize that cocaine and Tat synergistically disrupts metabolic and bioenergetic pathways in the brain, disturbing neuronal cell function, affecting oligodendrocyte status and their communication with neurons, thereby promoting neurologic/neurocognitive disorders in cocaine/HIV-1 cohorts. Here, we have developed a comprehensive, integrated multidisciplinary research program composed of three projects led by experts in neuroscience of HIV-1, cocaine research, metabolic pathways and mitochondria biology to investigate, in Project #1, the reciprocal interactions of cocaine/HIV-1 on glucose metabolism in macrophages and microglia, the cells that are primarily responsible for latency and productive HIV-1 infection in the brain an the release of viral and cellular toxic factors including HIV-1 Tat. In Project #2, we will investigate the impact of cocaine and HIV-1 Tat, released by infected cells on mitochondrial homeostasis in neurons by concentrating on genetics of mitochondrial DNA on mitochondrial bioenergetic pathways and ATP production, and biogenesis of mitochondria. In Project #3, we will focus our attention on the effects of cocaine and HIV-1 Tat on oligodendrocytes and the cross-talk between oligodendrocytes and neurons in relation to glucose metabolism, lipid biosynthesis and retinoic acid signaling. This program will be supported by a highly specialized, state-of- the art core facility: Mitochondria Physiology and Imaging Core (Core B) and will greatly benefit from the unique infrastructure offered by two NIH-funded centers, i.e. Center for Substance Abuse Research (CSAR) and Comprehensive NeuroAIDS Center (CNAC) at our institution. The outcome of this highly integrated, innovative and interactive research program will provide a panoramic view of the molecular and cellular events involving metabolic and bioenergetic pathway in cocaine and HIV-1 induced CNS disease, advance the field in and area that remains unexplored, and offer fundamental information toward the development of therapeutic molecules against HIV-1/cocaine induced CNS disease.